Ecklonia stolonifera is a brown alga that was shown to have antioxidant, anti-inflammatory, tyrosinase inhibitory, and chemopreventive activities. However, the molecular mechanisms underlying its anti-inflammatory activity remain unclear. In this study, we investigated the molecular mechanism of the anti-inflammatory action of E. stolonifera ethanolic extracts (ESE) using lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. ESE inhibited LPS-induced nitric oxide (IC(50) = 72 ± 1.9 μg/mL) and prostaglandin E(2) (IC(50) = 98 ± 5.3 μg/mL) production in a dose-dependent manner and suppressed the expression of inducible nitric oxide synthase and cyclooxygenase-2 in RAW 264.7 cells. ESE also reduced the production of pro-inflammatory cytokines in LPS-stimulated RAW 264.7 cells. LPS-induced nuclear factor-κB (NF-κB) transcriptional activity and NF-κB translocation into the nucleus were significantly inhibited by ESE treatment through the prevention of the degradation of inhibitor κB-α. Moreover, ESE inhibited the activation of Akt, ERK, JNK1/2, and p38 MAPK in LPS-stimulated RAW 264.7 cells. The main components with anti-inflammatory activity in ESE were identified as phlorofucofuroeckol A and B based on the inhibition of NO production. Our results indicate that ESE can be considered as a potential source of therapeutic agents for inflammatory diseases.